. Author manuscript; available in PMC: 2017 Jan 19.

Published in final edited form as: Nat Neurosci. 2016 Feb;19(2):206–219. doi: 10.1038/nn.4202

Table 1.

Energy homeostasis in Mc4r mutant mice

Mouse line	Body weight	Energy intake	Energy expenditure	Glucose homeostasis	Autonomic outflow	Other phenotypes	Ref.
Mc4r^−/− Mixed background	Increased body weight from 5 weeks	Hyperphagic. 46% increase in average daily consumption	NR	Hyperglycemic and hyperinsulinemic (more pronounced in males)	NR	Increased axial length. Normal serum corticosterone levels.	16
Mc4r^−/− Mixed background	Pair-fed male mice show normal body weight. Pair-fed female mice show intermediate body weight.	Non-pair-fed mice hyperphagic at 14 weeks of age (not at 10 weeks)	Reduced basal VO₂ consumption at 7 weeks (precedes obesity). Non-pair-fed males hypolocomotive during dark cycle. Normal basal body temperature and response to cold exposure	Non-pair-fed mice hyperglycemic and hyperinsulinemic. Pair-fed mice normal glucose and insulin levels	Insensitive to leptin-mediated BAT Ucp1 induction	NR	48
Mc4r^−/− Congenic BL/6 (3–5 generations)	Increased body weight. Exaggerated weight gain on HCD.	Hyperphagic. Normal body weight response to caloric restriction. Normal feeding response to overnight fasting. Increased consumption on high-fat diet.	Reduced basal VO₂ consumption. Reduced exergonic response to HCD. Increased respiratory exchange ratio on HCD. Normal basal body temperature and response to cold exposure.	Pre-obese mice are normoglycemic and normoinsulinemic. Obese mice show hepatic insulin resistance.	Reduced exergonic response to HCD not due to reduced SNS outflow to BAT	Normal body weight and feeding response to cold exposure. Reduced circulating triglycerides. Increased hepatic fatty acid synthesis.	47, 81, 91
Mc4r^−/− Mixed background	Increased body weight from 5 weeks	Hyperphagic from weaning	Pre-obese mice exhibit increased metabolic rate	NR	NR	NR	134
Mc4r^−/− Mixed background	NR	NR	NR	NR	NR	Increased circulating high- density lipoprotein	93
Mc4r^−/− Mixed obesity- resistant background	Increased body weight and adiposity from 5 weeks	Hyperphagic. Pre-obese mice responsive to anorectic effect of leptin.	NR	NR	Insensitive to leptin-mediated BAT Ucp1 induction	NR	135
Mc4r^−/− Mixed background	Increased body weight from 5 weeks	Insensitive to anorectic effects of MTII	Insensitive to exergonic effects of MTII. Hypolocomotive during the dark cycle.	NR	NR	NR	136
Mc4r^−/− Mixed background	NR	Insensitive to anorectic effects of MTII. Pre-obese mice responsive to anorectic effect of leptin. Obese mice unresponsive to anorectic effect of leptin. Mice sensitive to orexigenic effects of NPY.	NR	NR	NR	NR	137
Mc4r^−/− Mixed background (females)	NR	Insensitive to anorectic effects of CCK	NR	NR	NR	NR	138
Mc4r^−/− Mixed background	NR	Higher breakpoint in a progressive-ratio lever-pressing assay	NR	NR	NR	NR	50
Mc4r^−/− Mixed background	NR	NR	NR	NR	NR	No antisecretory response from VIP- stimulated intestinal L-cells. Reduced PYY release.	55
Mc4r^−/− Congenic BL/6	Increased body weight from 7 weeks and increased adiposity	Hyperphagic	NR	Hyperglycemic. Hyperinsulinemic.	NR	Obese mice normotensive, bradycardic, normal hemodynamic response to high salt diet. Obese and pair-fed mice insensitive to hypertensive effects of leptin.	86, 139
Mc4r^loxTB^/^loxTB Mixed background	Increased body weight from 4 weeks	Hyperphagic. Insensitive to anorectic effects of MTII.	Reduced VO₂ consumption	Hyperglycemic and hyperinsulinemic from 5 weeks of age	Normotensive	Increased axial length	53, 82
Mc4r^loxTB^/^loxTB	NR	NR	NR	Exaggerated fasting glucose levels and glucose intolerance during the dark cycle. Constant light conditions improves glycemia.	NR	NR	140
Mc4r^loxTB^/^loxTB Congenic 129 and mixed background	Increased body weight from 7 weeks	NR	NR	NR	NR	Reduced sensitivity to Roux-en-Y gastric bypass	56
Zp3-Cre:: Mc4r^loxTB^/^loxTB Mixed background	Normal body weight	NR	NR	NR	NR	NR	53
Nestin-Cre:: Mc4r^loxTB^/^loxTB Mixed background	Normal body weight	NR	NR	NR	NR	Normalized axial length	53
Sim1-Cre:: Mc4r^loxTB^/^loxTB Mixed background	60% reduction in body weight and reduced fat and lean mass	Normalized food intake. Re-sensitized to anorectic effect of MTII	Reduced VO₂ consumption. Hypometabolism precedes hyperphagia. Insensitive to exergonic effects of MTII.	Mildly improved serum glucose and insulin levels at 5 weeks. Normalized glucose levels and at improved insulin levels 12 weeks	Normotensive	Normalized axial length	53, 67, 82
Chat-ires-Cre:: Mc4r^loxTB^/^loxTB	10% reduction in body weight and reduced fat mass	Hyperphagic	Normalized VO₂ consumption	Mildly improved serum glucose and insulin levels. Insulin resistant.	Hypertensive during dark cycle	Increased axial length	69, 82
Phox2b-Cre:: Mc4r^loxTB^/^loxTB	No improvement in body weight or fat mass	Hyperphagic	No improvement in VO₂ consumption	No improvement in serum glucose levels. Normoinsulinemic and not insulin resistant	NR	Increased axial length	69
Sim1-Cre:: Mc4r^loxTB^/^loxTB:: vGlut2^loxP^/^loxP	No improvement in body weight or fat mass	Hyperphagic	No improvement in VO₂ consumption. Insensitive to exergonic effects of MTII	NR	NR	NR	67
vGlut2-ires-Cre:: Mc4r^loxTB^/^loxTB	Normalized body weight	Normalized food intake	Normalized VO₂ consumption	Normalized serum glucose and insulin levels		Normalized axial length	54
vGat-ires-Cre:: Mc4r^loxTB^/^loxTB	No improvement in body weight	NR	NR	NR	NR	NR	54
Oxt-ires-Cre:: Mc4r^loxTB^/^loxTB	No improvement in body weight	NR	NR	NR	NR	NR	54
Crh-ires-Cre:: Mc4r^loxTB^/^loxTB	No improvement in body weight	NR	NR	NR	NR	NR	54
Pdyn-ires-Cre:: Mc4r^loxTB^/^loxTB	No improvement in body weight	NR	NR	NR	NR	NR	54
Avp-ires-Cre:: Mc4r^loxTB^/^loxTB	No improvement in body weight	NR	NR	NR	NR	NR	54
Drd1-cre:: Mc4r^loxTB^/^loxTB	Mild improvement in body weight and fat mass	Mild improvement in hyperphagia on chow. Reduction in meal size. Partial restoration of MTII sensitivity.	No improvement in VO₂ consumption	NR	NR	NR	49
Mc4r^loxP^/^loxP	Normal body weight	NR	NR	NR	NR	NR	54
EIIa-Cre:: Mc4r^loxP^/^loxP	Increased body weight from 5 weeks. Increased fat and lean mass.	Hyperphagic	NR	NR	NR	Increased axial length	54
Sim1-Cre:: Mc4r^loxP^/^loxP	Increased body weight from 6 weeks. Increased fat mass.	Hyperphagic	NR	NR	NR	Increased axial length	54
Chat-ires-Cre:: Mc4r^loxP^/^loxP	Increased body weight from 8 weeks. 40% increase by 20 weeks. Increased fat and lean mass. Increased sensitivity to HCD.	Normal feeding behavior. Hyperphagic on HCD. Reduced Ucp1 induction on HCD.	Reduced energy expenditure, intermediate to Mc4r^Δ/Δ. Reduced diet-induced hypermetabolism. Normal body temperature	Hyperglycemia and hyperglucagonemia comparable to Mc4r^Δ/Δ. Intermed iate hyperinsulinemia. Insulin resistant.	Reduced thermogenic response to cold exposure. Reduced Ucp1 induction on cold exposure or high-calorie diet.	Normal axial length	70
Phox2b-Cre:: Mc4r^loxP^/^loxP	No effect on body weight or composition. Normal sensitivity to HCD.	Normal feeding behavior on HCD	Normal exergonic response to a HCD	Normoglycemic and normoglucagonemic. Hyperinsulinemic.	Normal Ucp1 induction	NR	70

Phenotypes arising from the germline and conditional genetic manipulations of mouse Mc4r expression. NR, not reported; CCK, cholecystokinin; HCD, high calorie diet.